Epithelial-mesenchymal crosstalk in intestinal polyp formation

肠息肉形成中的上皮-间质串扰

• 批准号: 10604626
• 负责人: Mei Lan Li
• 金额: $ 4.77万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604626
• 关键词: Acute; Adolescent; Agonist; Architecture; Biology; Cell Differentiation process; Cell Proliferation; Cells; Choristoma; Collaborations; Data; Disease; Epithelial Cells; Epithelium; Equilibrium; Event; Fibroblasts; Fluorescent in Situ Hybridization; Gene Expression; Germ-Line Mutation; Goals; Growth; Heterogeneity; Homeostasis; Inherited; Intestinal Cancer; Intestinal Polyposis; Intestinal Polyps; Intestines; Juvenile polyposis syndrome; Knowledge; Lead; Ligands; Link; Maintenance; Measures; Mediating; Mesenchymal; Modeling; Mus; Muscle; Pathogenesis; Pathogenicity; Pattern; Polyps; Population; Proliferating; Public Health; Regulation; Reporter; Reporting; Risk; Role; Shapes; Signal Transduction; Small Intestines; Spatial Distribution; Specific qualifier value; Syndrome; System; Testing; Tissues; Universities; Villus; WNT Signaling Pathway; antagonist; carcinogenesis; cell type; confocal imaging; epithelial stem cell; gastrointestinal; insight; intestinal epithelium; intestinal homeostasis; loss of function; mouse model; novel; overexpression; polyposis; prevent; segregation; single molecule; smoothened signaling pathway; stem cell niche; stem cell proliferation; stem cells; stemness; transcriptomics

Project Summary Epithelial-mesenchymal interactions within the mammalian small intestine regulate stem cell dynamics for accurate balance between cell proliferation and differentiation. Mesenchymal cells, particularly fibroblasts, secrete signals to regulate epithelial cells, such as Wnt for epithelial growth and Bmp for epithelial differentiation. However, how fibroblasts themselves are regulated remains unknown. Studying fibroblast biology is critical, as fibroblasts can drive intestinal polyposis, which is a common gastrointestinal condition with epithelial hyperproliferation linked to elevated risk of intestinal carcinogenesis. Human juvenile polyposis and hereditary mixed polyposis syndromes are associated with germline mutations that lead to Bmp signaling loss. Despite common feature of epithelial overgrowth in polyps, mouse studies have demonstrated that specific loss of Bmp signaling from fibroblasts, not from intestinal epithelium, is sufficient to drive polyp formation. The mechanisms by which Bmp signaling loss from fibroblasts drives uncontrolled epithelial growth in developing polyps remain unclear. The overall objectives are to (i) determine the underlying fibroblast-driven mechanisms of epithelial hyperproliferation upon Bmp signaling loss in Aim 1, and to (ii) define the role of Bmp signaling to fibroblast identity specification and maintenance in Aim 2. To induce polyp formation, an inducible Bmp signaling loss-of- function mouse model through overexpression of the Bmp antagonist Noggin is utilized. Strikingly, within three days of Bmp signaling inhibition, the intestine first undergoes an architectural change, an ectopic tissue fold, that does not involve epithelial hyperproliferation. Rather, epithelial proliferation only increases after several weeks of Bmp signaling loss. My finding is the first to suggest the role of tissue architecture in regulating stem cell dynamics and epithelial homeostasis. The central hypothesis is that alterations in specific subset(s) of intestinal fibroblasts disrupt local tissue architecture, resulting in polyp formation. The long-term goal is to understand how spatially segregated, unique fibroblast subtypes regulate tissue homeostasis and contribute to disease pathogenesis. As my preliminary data demonstrate that fibroblasts mislocalize and accumulate towards stem cells, coinciding with ectopic fold formation, Aim 1 will examine changes in fibroblast-secreted Wnt ligand distribution within the epithelium, and whether these changes result in epithelial overgrowth in developing polyps. This aim will deepen our foundational knowledge on dysregulated crosstalk between epithelial cells and niche players in intestinal pathogenesis. Aim 2 will employ a spatial transcriptomic approach to examine the effects of Bmp signaling loss to fibroblast gene expression profiles and localization during polyp initiation and progression. It will reveal the requirements for Bmp signaling in specifying/maintaining fibroblast subtype identity and spatial distribution in intestinal homeostasis, and that when disrupted, drives epithelial hyperproliferation in developing polyps. Completion of this project will advance our knowledge on fibroblast regulation and stem cell niche dynamics, which could lead to the identification of novel target cell types in preventing/treating intestinal cancers.

哺乳动物小肠上皮-间充质相互作用调节干细胞